Thrombin is a serine protease that plays an essential role during blood clotting. Clotting is initiated when blood vessel walls are damaged and subendothelium proteins are released, inducing a cascade of events that includes the activation of platelets and conversion of prothrombin to thrombin. The activated platelets and thrombin recruit more platelets and propagate local inflammation through leukocyte and endothelial cell activations, fueling thrombosis. While thrombin is central to the formation of a thrombus early on, it continues to further activate platelets and inflammatory pathways. Thrombin is the most potent physiologic platelet agonist known.
Anticoagulants are substances that prevent blood clotting, and include the class of anticoagulants that are direct thrombin inhibitors. One such thrombin inhibitor is bivalirudin (Angiomax®), which directly inhibits thrombin by specifically binding to both its catalytic site and its anion-binding exosite. Angiomax® is FDA-approved to treat patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA); to administer with the provisional use of glycoprotein IIb/IIIa inhibitor for use as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI); and to treat patients with, or at risk of, heparin-induced thrombocytopenia (HIT) or heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) undergoing PCI. Angiomax® Prescribing Information at 2. Angiomax® is intended for use with aspirin and has been studied only in patients concomitantly receiving aspirin. Id. Furthermore, Angiomax® (Angiox® in Europe) has received European approval for use as an anticoagulant in patients with heart attacks (so-called ST-segment elevation myocardial infarction (STEMI)) undergoing emergency heart procedures called primary PCI.
Angiomax® is delivered through intravenous administration and supplied as a sterile, lyophilized drug product in a single-use vial. Id. at 1, 4. Each single-use vial contains 250 mg of bivalirudin, 125 mg mannitol, and sodium hydroxide to adjust the pH to about 5-6 (equivalent of approximately 12.5 mg sodium). Id. When reconstituted with a sterile aqueous solution for injection, Angiomax® yields a clear to opalescent, colorless to slightly yellow solution. Id.
When Angiomax® was approved by FDA in December of 2000, it was prepared by a compounding process whereby a solution comprising sodium hydroxide (“NaOH solution”) was added to a solution comprising bivalirudin salt (“bivalirudin solution”) to form a compounding solution. The bivalirudin solution had a pH of between about 1.8 to about 2.8, and the addition of the NaOH solution resulted in a compounding solution that had a final pH of between about 5 and about 6. However, as the NaOH solution was added to the bivalirudin solution, the pH of the resulting compounding solution passed through the isoelectric point (“pI”) of bivalirudin (about 3.6), where bivalirudin had limited solubility and a portion of bivalirudin precipitated as a dense material, forming a “gum-like” gel. Once bivalirudin gelled or became “gum-like,” there was a significant delay as bivalirudin had to be re-dissolved. Such a delay extended production time while manufacturer operators tried to re-dissolve the “gum-like” bivalirudin. In addition, this compounding process also resulted in inconsistent and sometimes elevated levels of impurities such as Asp9-bivalirudin as a result of localized sites of high pH in the compounding solution that were produced when the precipitate formed.
Currently, Angiomax® is prepared according to the process described in U.S. Pat. No. 7,598,343 (“the '343 patent”). The '343 patent teaches a process wherein the method of preparing pharmaceutical batch(es) or pharmaceutical formulation(s) of bivalirudin may comprise (1) dissolving bivalirudin salt in a solvent to form a bivalirudin solution; (2) efficiently mixing a pH-adjusting solution with the bivalirudin solution to form a compounding solution; and (3) removing the solvent from the compounding solution. See, e.g., '343 patent, col.6,1.61-col.12,1.9.
The '343 patent overcomes many of the problems associated with the prior process, which formed a dense precipitate in the compounding solution that was difficult to manage, created a high pH, and generated Asp9-bivalirudin. '343 patent, col.9, 11.3-9. The '343 patent solved the prior problems by efficiently mixing the pH-adjusting solution with the bivalirudin solution to form an amorphous precipitate. Id. at 11.10-17. The amorphous character allows for a more rapid re-dissolution of the precipitate and better control of pH throughout the compounding process. Id. at 11.12-14. As a result, the process described in the '343 patent minimizes Asp9-bivalirudin generation in the compounding solution. See id. at 11.34-35. Yet, even though this method provides a significant manufacturing improvement, a precipitate, albeit amorphous, is nonetheless formed.
A different process for preparing bivalirudin drug product is discussed in CN Publication No. 101244043 (“the '043 publication”). The '043 publication describes a process that involves the steps of (1) dissolving bivalirudin and auxiliary materials in water; (2) adjusting the pH of the solution with a pH conditioner; (3) filtering the solution through 0.22-μm membrane, and (4) freeze-drying the solution to obtain a dried powder. '043 publication, p. 4, ¶2. The '043 publication further discusses dissolving bivalirudin (60-68 mg/mL) in water and adding a solution of sodium carbonate to adjust the pH between 4.5 and 6.5. Id. at p. 4-6. The '043 publication indicates that bivalirudin is “easily soluble in water,” and that the dissolved bivalirudin is brought to a pH between 4.5 and 6.5 by addition of a pH conditioner (e.g., sodium carbonate or sodium bicarbonate). Id. at 1. Therefore, given these conditions of bivalirudin solubility, final pH, and type of pH conditioner, the pH of the bivalirudin solution initially should be below the pI of bivalirudin and then pass through the pI to reach the desired pH. Consequently, this process risks the formation of a precipitate.
Taken together, the known processes for preparing a dried bivalirudin drug product should pass through the isoelectric point and result in the formation of a precipitate, which, as described above, can delay production, require human intervention, and cause loss of drug product due to high Asp9-bivalirudin levels. In general, delays in production and human error can heavily impact drug manufacturing costs. Therefore, a method that reduces production delays and minimizes human intervention will enhance product quality and reduce operation costs. In turn, this improvement will better meet the prescriber and patient demands for a dried bivalirudin drug product.